Supplemental Digital Content
Surgery and Anesthesia Exposure is not a Risk Factor for Cognitive Impairment after Major Noncardiac Surgery and Critical Illness
Christopher G Hughes, Mayur B Patel, James C Jackson, Timothy D Girard, Sunil K Geevarghese, Brett C Norman, Jennifer L Thompson,Rameela Chandrasekhar, Nathan E Brummel, Addison K May, Mark R Elstad, Mitzi L Wasserstein, Richard B Goodman, Karel G Moons, Robert S Dittus, E Wesley Ely, and Pratik P Pandharipande for the MIND-ICU and BRAIN-ICU investigators
Table of Contents
A. Inclusion and Exclusion Criteria B. Confounders
C. Multiple Imputation
D. Supplemental Figure 1. Enrollment and Follow-up
E. Anesthesia/Surgery Characteristics and Supplemental Table 1 F. References
A. Inclusion and Exclusion Criteria
We enrolled adult patients within 72 hours of a medical or surgical intensive care unit (ICU) admission who were being treated for respiratory failure or shock, including after major surgical procedures and non-surgical medical illnesses. Respiratory failure included the use of invasive mechanical ventilation, noninvasive positive pressure ventilation, nonrebreather mask, or heated high-flow nasal cannula. Shock included the use of intra-aortic balloon pump,
dopamine ≥7.5 mcg/kg/min, dobutamine ≥5 mcg/kg/min, norepinephrine ≥5 mcg/min,
phenylephrine ≥75 mcg/min, epinephrine at any dose, milrinone at any dose if used with another vasopressor, or vasopressin ≥0.03 units/min if used with another vasopressor.
We excluded patients with recent critical illness which included >5 ICU days within 30 days prior to current ICU admission or >72 hours of respiratory failure or shock during current ICU admission. We excluded patients in moribund state which was defined as life expectancy
<24 hours or decision to not pursue restorative therapies by the medical team. We excluded patients who were unable to be reliably assessed for delirium which included inability to speak English, blindness, and deafness. We excluded patients with high likelihood of preexisting cognitive deficits which included a diagnosis of severe dementia, suspected anoxic brain injury, or cardiac surgery within 3 months. We excluded patients with admission for stroke or
neurological surgery. We excluded patients with limited outpatient follow-up opportunity which included active substance abuse or psychiatric disorder, homelessness, or residence >200 miles from the enrolling center. We excluded patients who we were unable to obtain written informed consent from the patient or surrogate. We obtained consent from patients once competent if initial consent was obtained from a surrogate.
B. Confounders
Pre-existing cognitive deficit was assessed with the Short Form Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-SF)1 score administered by trained research personnel. The IQCODE-SF has a sensitivity >0.80 to identify mild cognitive impairment2, 3 and
>0.90 in heterogeneous populations to identify adults in the general hospital setting at risk of dementia.4 This high sensitivity implies that very few patients with pre-existing cognitive deficits would have gone undetected in our study. Trained research personnel assessed patients for acute brain dysfunction (coma and delirium) using the Richmond Agitation-Sedation Scale (RASS)5 and the Confusion Assessment Method for the ICU (CAM-ICU)6 twice daily in the ICU and once daily after ICU discharge. Patients with a RASS of -4 or -5 were considered comatose.
Patients without coma (i.e., RASS of -3 or more awake) positive on the CAM-ICU were
considered delirious. We defined severe sepsis as ≥2 systemic inflammatory response syndrome criteria and organ dysfunction due to confirmed or suspected infection. We measured hypoxemia as the number of 15 minute intervals with oxygen saturation <90% on pulse oximetry. We calculated severity of illness as the mean Sequential Organ Failure Assessment Score7 for the hospital stay. In order to quantify opioid, sedative, and antipsychotic drug exposure, we calculated mean daily doses of opioids in fentanyl equivalents in mcg, mean daily doses of benzodiazepines in midazolam equivalents in mg, mean daily doses of propofol in mg, mean daily doses of dexmedetomidine in mcg, and mean daily doses of haloperidol in mg. We used the following conversions for fentanyl and midazolam equivalents:
1. 100 mcg fentanyl = 0.75 mg hydromorphone = 5 mg morphine 2. 2.5 mg midazolam = 1 mg lorazepam = 5 mg diazepam
2
In models including drug exposure, drug doses were cube-root transformed to reduce the influence of extreme outliers.
C. Multiple Imputation
In order to reduce bias from missing data, we used multiple imputation to include in our analyses any patient who had some missing covariates or who had at least partially completed cognitive assessments. No imputations were performed for completely missing cognitive assessments. Overall, imputed data was utilized in <7% of subjects at 3 months and <5% of subjects at 12 months.Multiple imputation was performed 10 times to generate 10 complete data sets. These 10 complete data sets were analyzed and the results from all 10 imputed datasets were pooled for overall inference using Rubin’s rules which account for the uncertainty associated with imputed values.8
D. Supplemental Figure 1. Enrollment and Follow-up
Cognitive assessments were obtained after discharge in 494 patients at 3 months and in 413 patients at 12 months. Cognitive assessments were obtained in a total of 534 patients after discharge.
E. Anesthesia/Surgery Characteristics
Anesthesia/surgery exposure characteristics for the 233 surgical patients with additional analyses are listed.
Supplemental Table 1
Type of surgery (%)
Gastrointestinal 44%
Soft tissue 11%
Transplant 11%
Thoracic 7%
Orthopedic 7%
Otolaryngology 6%
Vascular 5%
Urology/gynecology 4%
Other 5%
Emergent surgery (%)
Yes 60%
No 40%
Number of surgeries (%)
1 63%
2 19%
3 11%
≥4 7%
Total duration of anesthesia (min) 305 (146, 461) Anesthetic agent used (%)
Isoflurane 61%
Sevoflurane 21%
Desflurane 18%
F. References
4
1. Jorm AF. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): development and cross-validation. Psychol Med. 1994;24:145-153.
2. Isella V, Villa L, Russo A, et al. Discriminative and predictive power of an informant report in mild cognitive impairment. J Neurol Neurosurg Psychiatry. 2006;77:166-171.
3. Li F, Jia XF, Jia J. The Informant Questionnaire on Cognitive Decline in the Elderly individuals in screening mild cognitive impairment with or without functional impairment. J Geriatr Psychiatry Neurol. 2012;25:227-232.
4. Harrison JK, Fearon P, Noel-Storr AH, et al. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the diagnosis of dementia within a secondary care setting. Cochrane Database Syst Rev. 2015;3:CD010772.
5. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166:1338- 1344.
6. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU).
JAMA. 2001;286:2703-2710.
7. Ferreira FL, Bota DP, Bross A, et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286:1754-1758.
8. Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons;
1987.
